The Effect of Body Weight Changes on Total Plasma Clozapine Concentrations Determined by Applying a Statistical Model to the Data From a Double-Blind Trial.

PURPOSE/BACKGROUND: Some therapeutic drug monitoring studies suggest that increased weight is associated with small increases in clozapine concentrations. The goal of this study was to reanalyze a US double-blind study using a sophisticated statistical model to test whether weight gains from baseline or increases in percentage of body fat from baseline, computed from a published equation, are associated with increased total plasma clozapine concentrations after controlling for the effects of smoking and sex. METHODS/PROCEDURES: Using data from a multidosage randomized double-blind US clozapine trial previously published, a random intercept linear model of steady-state total plasma clozapine concentrations was fitted to 424 concentrations from 47 patients. FINDINGS/RESULTS: After adjusting for sex and smoking, (1) a 1-kg gain in body weight during clozapine treatment was significantly associated with a 1.4% increase in total plasma clozapine concentrations (95% confidence interval = 0.55 to 2.3) and (2) a 1-point increase in percentage of body fat during clozapine treatment was significantly associated with a 5.4% increase in total clozapine concentration (2.5 to 8.3) in females and 1.4% (-1.1 to 4.0) in males. IMPLICATIONS/CONCLUSIONS: As hypothesized, weight increases during clozapine treatment, which probably reflect increases in fat tissue, were associated with increases in total plasma concentrations. Pending further replication in other samples, it seems likely that clozapine may deposit in body fat and that this may decrease clozapine clearance. This change may be small in most patients but may be clinically relevant in females with major gains in body fat.

Weight gain during a double-blind multidosage clozapine study.

Possible variables associated with weight gain during clozapine treatment include dosing, treatment duration, baseline body mass index (BMI), sex, and plasma norclozapine concentrations. Weight gains during a double-blind, randomized clozapine study using 100-, 300-, and 600-mg/d doses were analyzed. It was hypothesized that weight gain was associated with baseline BMI, clozapine dosing, and demographic factors. The possible contribution of plasma clozapine and norclozapine concentrations was explored. Fifty treatment-refractory schizophrenia patients were randomized to 100-, 300-, or 600-mg/d doses of clozapine for a 16-week, double-blind treatment in a research ward. Nonresponsive patients went onto a second and/or a third 16-week, double-blind treatment at the other doses. Weights of patients were measured every week. During the first clozapine treatment, weight gain varied across 3 baseline BMI categories (normal-weight patients [4.1 kg, P < 0.001], overweight patients [2.6 kg, P = 0.05], and obese patients [0.36 kg, not significant]) and according to dosing (600 mg/d [4.4 kg], 300 mg/d [2.6 kg], and 100 mg/d [1.3 kg]). Sex had no effect after controlling for baseline BMI and dose, but the African-American race had a strong significant effect despite the small number of African Americans (n = 6). At the end of the first clozapine treatment, plasma norclozapine concentration was not significantly correlated with weight gain in the total sample (r = 0.16, P = 0.32, n = 43), but seems to be strongly correlated in nonsmokers. Despite its limitations, this study indicates that baseline BMI, dosing, and, possibly, the African-American race may be major determinants of clozapine-induced weight gain.

Does clozapine decrease smoking?

McEvoy et al.'s study in 1999, which used cotinine levels but had limited power, suggested that clozapine treatment may be associated with a mild smoking decrease (particularly when plasma clozapine levels are > 150 ng/ml). Some naturalistic studies also suggest that clozapine treatment may be associated with a mild smoking decrease. The present study included 38 schizophrenic daily smokers from a double-blind clozapine trial. Five analyses were tested for significant decreases in plasma cotinine levels from a haloperidol baseline to: (1) the end of clozapine trials regarding clozapine doses (100, 300 or 600 mg/day), (2) the end of the clozapine trial where the highest plasma clozapine level was achieved, (3) the end of the clozapine trial where a clozapine level in the 150-450 ng/ml range was achieved, (4) the end of the first clozapine trial regardless of clozapine dose, and (5) the end of the last clozapine trial in the study. The first and straightforward analysis by dose showed no clozapine effects on smoking. The second and the third analyses (an attempt to mimic the design by McEvoy et al. [McEvoy, J.P., Freudenreich, O., Wilson, W.H., 1999. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiat. 46, 125-129.]) also indicated that there was not a significant effect of clozapine on smoking. The fourth and five analyses were also negative. None of the five analyses in our clozapine trial demonstrated that clozapine had major effects on smoking. This study cannot rule out that in some subjects, clozapine treatment may be associated with a small decrease in smoking. New prospective longitudinal studies using repeated cotinine and clozapine levels are needed to explore whether clozapine may reduce smoking in some patients.

Plasma clozapine concentration coefficients of variation in a long-term study.

Kurz et al. conducted the first study of the intra-individual variability of clozapine plasma concentrations but did not take into account the effect of smoking and co-medication. As patients were receiving varying doses, Kurz et al. standardized plasma levels by using a plasma level/dose/kg ratio. In 15 patients, the mean coefficient of variation (CV) was 53% (S.D. = 21). In this new study, plasma clozapine and norclozapine concentrations were measured every 2 weeks in 47 patients randomized to 100, 300, or 600 mg/day for 16-week double-blind clozapine trials under controlled conditions (stable smoking, limited co-medication and absence of caffeinated beverages). For 100, 300 and 600 mg/day, the respective mean CVs for plasma clozapine concentrations were 23% (S.D. = 14), 19% (S.D.= 11) and 18% (S.D. = 8). For the combined concentrations of clozapine and norclozapine, the respective mean CVs were 20% (S.D. = 13), 16% (S.D. = 9) and 15% (S.D. = 7). Under 100 mg/day, the mean CV for clozapine concentrations was significantly higher for heavy smokers than non-heavy smokers (32%, S.D. = 3 vs. 19%, S.D. = 8) (p = 0.03). Studies of CVs in other environments are needed. Clozapine CVs may be important in order to understand the importance of variations around the therapeutic range and to interpret drug interactions above the usual noise of measuring plasma concentrations.

Haloperidol half-life after chronic dosing.

In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration.